A significant challenge to efforts aimed at inducing effective antitumor immune responses is that CD8(+) T cells, which play a prominent role in these responses, may be unable to respond to tumors that lack costimulatory signals and that are protected by an immune suppressive environment such as that mediated by TGF-beta produced by tumor cells themselves or by infiltrating Tregs, often resulting in tolerance or anergy of tumor-specific T cells. Here we show that the in vitro activation of Cblb(-/-) CD8(+) T cells does not depend on CD28 costimulation and is resistant to TGF-beta suppression. In vivo studies further demonstrated that Cblb(-/-) mice, but not WT controls, efficiently rejected inoculated E.G7 and EL4 lymphomas that did not express B7 ligands and that introduction of the Cblb(-/-) mutation into tumor-prone ataxia telangiectasia mutated-deficient mice markedly reduced the incidence of spontaneous thymic lymphomas. Immunohistological study showed that E.G7 tumors from Cblb(-/-) mice contained massively infiltrating CD8(+) T cells. Adoptive transfer of purified Cblb(-/-) CD8(+) T cells into E.G7 tumor-bearing mice led to efficient eradication of established tumors. Thus, our data indicate that ablation of Cbl-b can be an efficient strategy for eliciting immune responses against both inoculated and spontaneous tumors.